Solvation of a tetrapeptide, NAc-Ser-Phe-Val-Gly-OMe (1), in water and in water/alcohol mixtures with 2,2,2-trifluoroethanol (TFE)/water or ethanol (ETH)/water has been studied by diffusion NMR and intermolecular NOE measurements. The experimental results were compared with those obtained from detailed Molecular Dynamics (MD) calculations. Independently, all three methods revealed preferential solvation on the surface of the peptide by TFE in the water/TFE mixtures, but not by ETH in the water/ETH mixtures. The MD calculations show that the TFE concentration coating the peptide is higher than that in the bulk, while for ethanol, the concentration is nearly equal to that in the bulk. Calculated site-specific preferential solvation data between TFE, ETH, and water with the different peptide groups have been compared with the NMR data and shown to be in general agreement with the experimental facts.

An all-atom model of 1,1,1,3,3,3-hexafluoro-propan-2-ol (HFIP) for use in molecular dynamics simulation studies is proposed. The model was parametrized by fitting to the experimental density, pressure, and enthalpy of vaporization of the pure liquid at 298 K. The model was then tested by comparison against other experimental thermodynamic and kinetic properties of the pure liquid. Mixtures with SPC water were also investigated. Overall, reasonable agreement with the available experimental data for the neat liquid and for mixtures with SPC water was found. A tendency for HFIP to cluster in SPC water was observed in qualitative agreement with experimental observations. The effect of HFIP on the secondary structure of peptides was also studied. Two simulations of the peptide Melittin, in pure water and in 30% v/v HFIP, demonstrate the helix stabilizing effect of HFIP.

A new model for 2,2,2-trifluoroethanol is proposed. It is a 7-atom model with the methylene group treated as an united atom. The model was optimized to reproduce the physicochemical properties of the pure liquid. The properties of the new model were compared with the available experimental data over a range of temperatures. Furthermore, mixtures with the SPC water model were simulated to assess the ability to reproduce available thermodynamic and kinetic data as well as dielectric properties. The model provides a good agreement with experimental data for the neat liquid and for mixtures with water.

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The combination of the unique physical and chemical properties of fluorine with proteinogenic amino acids represents a new approach to the design of biologically active compounds including peptides with improved pharmacological parameters. Therefore, the development of routine synthetic methods which enable the effective and selective introduction of fluorine into the desired amino acids from readily available starting materials is of significant synthetic importance. The scope of this critical review is to summarize the most frequently employed strategies for the synthesis of alpha-difluoromethyl and alpha-trifluoromethyl substituted alpha-amino acids (114 references).